JPS649288B2 - - Google Patents
Info
- Publication number
- JPS649288B2 JPS649288B2 JP53135643A JP13564378A JPS649288B2 JP S649288 B2 JPS649288 B2 JP S649288B2 JP 53135643 A JP53135643 A JP 53135643A JP 13564378 A JP13564378 A JP 13564378A JP S649288 B2 JPS649288 B2 JP S649288B2
- Authority
- JP
- Japan
- Prior art keywords
- carnitine
- acetyl
- propionyl
- fatigue
- heart
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 230000002107 myocardial effect Effects 0.000 claims description 7
- 230000000747 cardiac effect Effects 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 206010002660 Anoxia Diseases 0.000 claims description 2
- 241000976983 Anoxia Species 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010021143 Hypoxia Diseases 0.000 claims description 2
- 230000007953 anoxia Effects 0.000 claims description 2
- 206010003119 arrhythmia Diseases 0.000 claims description 2
- 230000006793 arrhythmia Effects 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 5
- UFAHZIUFPNSHSL-MRVPVSSYSA-N O-propanoyl-L-carnitine Chemical compound CCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C UFAHZIUFPNSHSL-MRVPVSSYSA-N 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000001426 cardiotropic effect Effects 0.000 description 4
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 208000019622 heart disease Diseases 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 229960001518 levocarnitine Drugs 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000002929 anti-fatigue Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000033764 rhythmic process Effects 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229960004203 carnitine Drugs 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 230000009090 positive inotropic effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000006538 anaerobic glycolysis Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000002371 cardiac agent Substances 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 231100000457 cardiotoxic Toxicity 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000004041 inotropic agent Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 229940113601 irrigation solution Drugs 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- LKPLKUMXSAEKID-UHFFFAOYSA-N pentachloronitrobenzene Chemical compound [O-][N+](=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl LKPLKUMXSAEKID-UHFFFAOYSA-N 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- -1 propionyl ester Chemical class 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Description
本発明は心臓疾患治療剤、更に詳しくはｌ―カ
ルニチンのアセチルまたはプロピオニルエステル
を有効成分とする新規心臓疾患治療剤に関する。
本発明はアセチルまたはプロピオニル―ｌ―カ
ルニチン（特にアセチル―ｌ―カルニチン）を、
酸素欠乏症、虚血、心臓毒型の心臓疾患の治療お
よび連続的疲労時の心臓水準の酸素要求量が増大
するすべての場合の処置における有効成分として
使用する新規心臓疾患処置剤に指向されるもので
ある。
従来、ｄ，ｌ―カルニチン類を脂質代謝疾患お
よび筋ジストロフイー疾患を治療するため、少児
科の領域で使用されていることはよく知られてい
る。
本発明者は最近、ｄ，ｌ―カルニチン類が向心
臓特性を示し、心臓律動の疾患に特有な病理徴候
を好ましく治ゆさせ得ることを見出した。本発明
者は更にカルニチンのアシル誘導体（特にアセチ
ル―ｌ―カルニチン）の向心臓特性に関する薬理
効果を検討するため、ｄ，ｌ―カルニチンとアセ
チル―ｌ―カルニチンの薬理効果を比較した結
果、ｄ，ｌ―カルニチンに比し、アセチル―ｌ―
カルニチンは、より明らかな向心臓特性とすぐれ
た許容性を発揮することを見出した。
次に本発明のアセチル―ｌ―カルニチンの薬理
特性について詳述する。
(1) 急性毒性
アセチル―ｌ―カルニチンを雄マウスおよび雄
ラツトに静脈内投与して観察したLD50値とｄ，
ｌ―カルニチンを同様の条件で観察したLD50値
を比較してアセチル―ｌ―カルニチンの許容性を
試験した。LD50値はリツチフイールド（Lich
field）およびウイルコクソン（Wilcoxon）法に
より算出した。結果を第１表に示す。
The present invention relates to a therapeutic agent for heart disease, and more particularly to a novel therapeutic agent for heart disease containing an acetyl or propionyl ester of l-carnitine as an active ingredient. The present invention uses acetyl or propionyl-l-carnitine (especially acetyl-l-carnitine),
Directed to novel cardiac disease treatment agents for use as active ingredients in the treatment of anoxic, ischemic, cardiotoxic types of heart disease and in the treatment of all cases where cardiac level oxygen demand increases during continuous fatigue. It is. It is well known that d,l-carnitines have been used in the pediatric field to treat lipid metabolic diseases and muscular dystrophy diseases. The inventors have recently discovered that d,l-carnitines exhibit cardiotropic properties and can favorably cure the pathological signs characteristic of diseases of the heart rhythm. The present inventor further investigated the pharmacological effects of acyl derivatives of carnitine (particularly acetyl-l-carnitine) regarding their cardiotropic properties, and as a result of comparing the pharmacological effects of d,l-carnitine and acetyl-l-carnitine, d, Compared to l-carnitine, acetyl-l-
Carnitine was found to exhibit more pronounced cardiotropic properties and better tolerability. Next, the pharmacological properties of acetyl-l-carnitine of the present invention will be explained in detail. (1) Acute toxicity LD 50 values and d, observed after intravenous administration of acetyl-l-carnitine to male mice and male rats.
The tolerability of acetyl-l-carnitine was tested by comparing the LD 50 values observed for l-carnitine under similar conditions. LD 50 value is Lichfield (Lich
field) and the Wilcoxon method. The results are shown in Table 1.
【表】
(2) 摘出した心臓における心臓運動活性試験
ランゲンドルフ（Langndorff）法に従つて摘
出したラビツトの心臓に酸素処理したリンゲル液
を、温度38.2℃、流圧50ml水で注ぐ。ポリグラフ
により等尺性攣縮率、心電図および冠状動脈にお
ける循環を記録した。潅注液から酸素を除き、心
筋に対して代謝傷害を誘発させたところ、心筋収
縮力は徐々に80％まで低下した。このような酸素
欠乏状態を長びかせた場合において、心筋層の好
気的解糖作用が低下し、代謝による酸生成物が連
続的に集積する。これらの現象は、ピルビン酸の
消費を阻止すること、および乳酸脱水素酵素とし
てのピリジン酵素を抑制するので乳酸が利用され
ず、上記ピルビン酸を有効に乳酸に変換すること
ができないことに由来する。これらのことはすべ
て嫌気的解糖作用を招来し、酵素数量の増大に対
して影響を及ぼし、心筋の疲労を大ならしめる原
因となり、ますます危険性が増大する。このよう
な挙動により、心筋疲労の様相すべて判断するこ
とができる。これらを実験的挙動パラメータ、た
とえば筋収縮力、冠動脈の循環、心搏数、心臓の
律動により可視化することができる。
通常のリンゲル液（対照液）と種々の濃度の試
験化合物添加処理リンゲル液にそれぞれ酸素を供
給し、40分間に渡つて各種パラメータを記録し
た。心筋収縮力の百分率（％）を第２表に示す。[Table] (2) Cardiomotor activity test on the excised heart Pour oxygenated Ringer's solution into the excised rabbit heart according to the Langendorff method at a temperature of 38.2°C and a flow pressure of 50 ml of water. Isometric contraction rate, electrocardiogram and circulation in the coronary arteries were recorded by polygraph. When oxygen was removed from the irrigation fluid to induce metabolic damage to the myocardium, myocardial contractility gradually decreased by 80%. When such an oxygen-deficient state is prolonged, the aerobic glycolytic action of the myocardium decreases, and metabolic acid products continuously accumulate. These phenomena originate from the fact that the consumption of pyruvate is blocked and the pyridine enzyme as lactate dehydrogenase is inhibited, so lactic acid is not utilized and the above pyruvate cannot be effectively converted to lactic acid. . All of these things lead to anaerobic glycolysis, which affects the increase in the amount of enzymes, causing increased myocardial fatigue, and increasing the risk. Based on such behavior, all aspects of myocardial fatigue can be determined. These can be visualized by experimental behavioral parameters such as muscle contraction force, coronary circulation, heart rate, and heart rhythm. Oxygen was supplied to normal Ringer's solution (control solution) and Ringer's solution treated with test compounds at various concentrations, and various parameters were recorded over a period of 40 minutes. The percentage (%) of myocardial contractile force is shown in Table 2.
【表】
これらの数値は無酸素期間の中断10分後（心筋
恢復に計算した正の変力効果を表わす。この結果
はスチユーデント（Student）検定のｔ値で評価
したものであつて、同一濃度の潅注液で本発明の
アセチル―ｌ―カルニチンと従来のｄ，ｌ―カル
ニチンは統計的に有意差があり、前者の正の変力
効果は後者のそれより高いという結果を得た。両
化合物の潅注液は冠動脈循環および心搏数に敏感
な影響を与えることはなかつた。
それ故両化合物の向心臓作用は強心剤のそれと
異なる。更に明らかに抗不整脈効果が観察され
る。事実、酸素欠乏症を誘発することにより変化
した血脈洞律動は本発明におけるアセチル―ｌ―
カルニチンの場合に80％恢復する。これに対して
ｄ，ｌ―カルニチン円用いた場合の恢復は50％に
止まる。
(3) 抗疲労効果に関する実験
本発明のアセチル―ｌ―カルニチン、従来の
ｄ，ｌ―カルニチンおよび生理的溶液（対照液）
をそれぞれ雌ラツトに腹腔内投与して抗疲労効果
に関する実験を行なつた。薬剤処理後、ラツト15
分間（１期間）ごとに直径６cmの柵の中に入れ、
この柵を１分間16回転の速さで回転させる。回転
する柵内に180秒間以上留まることができるラツ
トの数（％）を観察した。各期間ごとの百分率を
第３表に示す。[Table] These values represent the positive inotropic effect calculated on myocardial recovery after 10 minutes of interruption of the anoxic period. These results were evaluated using the t-value of the Student's test, and the same concentration There was a statistically significant difference between acetyl-l-carnitine of the present invention and conventional d,l-carnitine in the irrigation solution, and the positive inotropic effect of the former was higher than that of the latter. The irrigant solution did not have a sensitive effect on coronary circulation and heart rate. Therefore, the cardiotropic effect of both compounds is different from that of the cardiotonic agents. Moreover, a clear antiarrhythmic effect is observed. In fact, anoxic The vascular sinus rhythm changed by inducing acetyl-l-
80% recovery with carnitine. On the other hand, when d,l-carnitine is used, recovery is only 50%. (3) Experiment on anti-fatigue effect Acetyl-l-carnitine of the present invention, conventional d,l-carnitine and physiological solution (control solution)
An experiment was conducted on the anti-fatigue effect by intraperitoneally administering each to female rats. After drug treatment, rat 15
They are placed in a 6cm diameter fence every minute (one period).
Rotate this fence at a speed of 16 revolutions per minute. The number (%) of rats that could remain in the rotating cage for more than 180 seconds was observed. Table 3 shows the percentages for each period.
【表】
上記効果をχ2検定により評価した結果、同等の
投与量でアセチル―ｌ―カルニチン類は従来の
ｄ，ｌ―カルニチン類より抗疲労活性が大であつ
て、両者の間に統計的有意差を認めた。
上記以外のアシル―ｌ―カルニチンとしてプロ
ピオニル―ｌ―カルニチンを用いて実験を行な
い、同様の結果を得た。このようなカルニチン誘
導体は次式で示すことができる：
〔Ｒはアセチルまたはプロピオニルを表わ
す。〕。
ｄ，ｌ―カルニチン類に比し、本発明のアセチ
ルまたはプロピオニル―ｌ―カルニチン類は耐容
性が良好であつて、心臓水準において高い薬理効
果を示す。それ故、本発明のアセチル―ｌ―カル
ニチンおよびプロピオニル―ｌ―カルニチンは特
に心筋無酸素症、不整脈、心不全、心疲労の治療
ならびに疲労が続くときに心臓水準のエネルギー
要求量が増大するすべての場合に対して有効であ
る。
次に実施例を挙げて本発明の向心臓薬の製造法
を説明する。本発明の向心臓薬は実施例に記載の
ものに限定されるものではなく、活性化合物およ
びその他の成分の種類と数量を適当に変えて本発
明の範囲に包含される他の薬剤を製剤することが
できる。
実施例 １
注射剤の製造：―
以下の記載の賦形剤にアセチル―ｌ―カルニチ
ン（たはプロピオニル―ｌ―カルニチン）を50〜
600mg／mlの濃度で含有せしめ注射用滅菌水性溶
液もしくは懸濁液を製造する。
(a) 注射剤に使用するための賦形剤：
低粘度ナトリウムカルボキシメチルセルロース
……10mg／ml、ポリソルベー80……４mg／ml、プ
ロピルパラベン……0.4mg／ml。
１バイアル当り１ml、２ml、５ml、10mlとなる
のに充分な注射液用蒸留水を加えてそれぞれのバ
イアル入り注射剤を製剤する。
(b) 静脈注射剤に使用するための賦形剤：
塩化ナトリウム……8.6ｇ／、塩化カリウム
……0.3ｇ／、塩化カルシウム……0.33ｇ／。
全量１となるのに充分な注射液用滅菌水を加
えてれぞれ50ml、100ml、250ml、500ml、1000ml
の静脈注射液用ビン入注射剤を製造する。
(c) ビン入経口投与剤のための賦形剤：
マンニトール……11mg／ml、ソルビトール……
600mg／ml、安息香酸ナトリウム……３mg／ml、
オレンジエキス……200mg／ml、要すればビタミ
ンB12……3mcｇ／ml。充分量の滅菌蒸留水を加
えて５ml、100mlのビン入経口投与剤を製剤する。
実施例 ２
錠剤の製造
殿粉45％、アビコール45％、タルク10％から成
る賦形剤にアセチル―ｌ―カルニチン（またはプ
ロピオニル―ｌ―カルニチン）20〜500mgを含有
する錠剤を製造する。
実施例 ３
カプセル剤の製造：
賦形剤を使用することなく、アセチル―ｌ―カ
ルニチン20〜500mgをカプセルに入れてカプセル
剤を製造する。[Table] As a result of evaluating the above effects using a χ test, it was found that acetyl-l-carnitines have greater anti-fatigue activity than conventional d,l-carnitines at the same dose, and there is no statistical difference between the two. A significant difference was observed. Experiments were conducted using propionyl-l-carnitine as an acyl-l-carnitine other than those mentioned above, and similar results were obtained. Such carnitine derivatives can be represented by the following formula: [R represents acetyl or propionyl. ]. Compared to d,l-carnitines, the acetyl- or propionyl-l-carnitines of the present invention are well tolerated and exhibit high pharmacological efficacy at the cardiac level. Acetyl-l-carnitine and propionyl-l-carnitine according to the invention are therefore particularly useful in the treatment of myocardial anoxia, arrhythmias, heart failure, cardiac fatigue and in all cases where the energy demands at the cardiac level increase when fatigue persists. It is valid for Next, the method for producing the cardiac drug of the present invention will be explained with reference to Examples. The cardiotropic drug of the present invention is not limited to those described in the Examples, but other drugs within the scope of the present invention may be formulated by appropriately changing the type and amount of the active compound and other ingredients. be able to. Example 1 Manufacture of injection: - Acetyl-l-carnitine (or propionyl-l-carnitine) is added to the excipient described below at a concentration of 50 to 50%.
A sterile injectable aqueous solution or suspension containing it at a concentration of 600 mg/ml is prepared. (a) Excipients for use in injections: Low viscosity sodium carboxymethylcellulose...10mg/ml, Polysorbate 80...4mg/ml, Propylparaben...0.4mg/ml. Each vial of injection is prepared by adding enough distilled water for injection to make each vial 1 ml, 2 ml, 5 ml, and 10 ml. (b) Excipients for use in intravenous injections: Sodium chloride...8.6g/, Potassium chloride...0.3g/, Calcium chloride...0.33g/. Add enough sterile water for injection to make a total volume of 50ml, 100ml, 250ml, 500ml, and 1000ml respectively.
The company manufactures bottled injections for intravenous injections. (c) Excipients for bottled oral preparations: mannitol...11 mg/ml, sorbitol...
600mg/ml, sodium benzoate...3mg/ml,
Orange extract...200mg/ml, vitamin B12 if necessary...3mcg/ml. A sufficient amount of sterile distilled water is added to formulate oral preparations in 5 ml and 100 ml bottles. Example 2 Preparation of Tablets Tablets containing 20 to 500 mg of acetyl-l-carnitine (or propionyl-l-carnitine) in an excipient consisting of 45% starch, 45% avicol, and 10% talc are prepared. Example 3 Production of capsules: Capsules are produced by placing 20-500 mg of acetyl-l-carnitine in capsules without using excipients.
Claims (1)
わす］ で示される化合物のｌ―異性体またはその医薬的
に許容される塩類を含有してなる、経口または非
経口投与可能な心筋酸素欠乏症、虚血、不整脈、
心疲労および心不全治療薬。[Claims] 1. As an active ingredient, the formula [wherein R represents acetyl or propionyl] A method for treating myocardial anoxia, ischemia, or orally or parenterally administrable containing the l-isomer of the compound represented by the formula or its pharmaceutically acceptable salts. arrhythmia,
Cardiac fatigue and heart failure treatment.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT51663/77A IT1143611B (en) | 1977-11-03 | 1977-11-03 | APPLICATION OF ACETYL-CARNITINE IN THE THERAPY OF CARDIAC AFFECTIONS OF / ANOXIC, ISCHEMIC, CARDIOTOXIC AND IN ARITHMIC SYNDROMES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5476830A JPS5476830A (en) | 1979-06-19 |
| JPS649288B2 true JPS649288B2 (en) | 1989-02-16 |
Family
ID=11275497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13564378A Granted JPS5476830A (en) | 1977-11-03 | 1978-11-02 | Cardial disease treating agent |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5476830A (en) |
| AU (1) | AU524988B2 (en) |
| BE (1) | BE871753A (en) |
| CH (1) | CH642847A5 (en) |
| DE (1) | DE2846335A1 (en) |
| FR (1) | FR2407717A1 (en) |
| IT (1) | IT1143611B (en) |
| NL (1) | NL7810818A (en) |
| ZA (1) | ZA785998B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2903579A1 (en) * | 1978-02-03 | 1979-08-09 | Sigma Tau Ind Farmaceuti | USE OF ACETYL CARNITINE AND OTHER ACYLDER DERIVATIVES OF CARNITINE FOR THE TREATMENT OF HYPERLIPOPROTEINEMIC AND HYPERLIMPIDAEMIA AND MEDICINAL PRODUCTS |
| IT1156741B (en) * | 1978-05-15 | 1987-02-04 | Sigma Tau Ind Farmaceuti | THERAPEUTIC APPLICATION OF CARNITINE AND SOME ACYLATED DERIVATIVES OF CARNITINE IN HEMODIALYSIS |
| IT1206954B (en) * | 1979-02-12 | 1989-05-17 | Sigma Tau Ind Farmaceuti | THERAPEUTIC AGENTS BASED ON AN ACIL DERIVATIVE OF CARNITINE FOR THE TREATMENT OF PERIPHERAL VASCULOPATHIES |
| US4346107A (en) * | 1979-02-12 | 1982-08-24 | Claudio Cavazza | Pharmaceutical composition comprising acyl-carnitine for the treatment of impaired cerebral metabolism |
| IT1116037B (en) * | 1979-04-23 | 1986-02-10 | Sigma Tau Ind Farmaceuti | ACIL CARNITINE ESTERS AND AMIDS THEIR PREPARATION PROCEDURES AND THERAPEUTIC USE |
| IT1150396B (en) * | 1982-12-09 | 1986-12-10 | Sigma Tau Ind Farmaceuti | USE OF ALCANOIL L-CARNITINE FOR THE THERAPEUTIC TREATMENT OF MYOPA TIE AND MUSCULAR DYSTROPHIES |
| JP2006347935A (en) * | 2005-06-15 | 2006-12-28 | Masanori Ogata | Pharmaceutical for preventing/treating disease related to inflammatory cytokine production |
| EP2096103A4 (en) | 2006-11-09 | 2012-11-21 | Mitsubishi Rayon Co | Process for production of betaine |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3624887A (en) * | 1970-03-02 | 1971-12-07 | Bunker Ramo | Pin and socket removal tool |
| US3830931A (en) * | 1972-11-06 | 1974-08-20 | Felice S De | Carnitine and its use in the treatment of arrhythmia and impaired cardiac function |
| US3968241A (en) * | 1972-11-06 | 1976-07-06 | Defelice Stephen L | Method of treating cardiac arrhythmias and of improving myocardial contractility and systolic rhythm with carnitive or a pharmaceutically acceptable salt thereof |
| JPS531812B2 (en) * | 1972-12-07 | 1978-01-23 | ||
| JPS5058213A (en) * | 1973-09-26 | 1975-05-21 |
-
1977
- 1977-11-03 IT IT51663/77A patent/IT1143611B/en active
-
1978
- 1978-10-24 ZA ZA785998A patent/ZA785998B/en unknown
- 1978-10-25 DE DE19782846335 patent/DE2846335A1/en not_active Withdrawn
- 1978-10-30 FR FR7830780A patent/FR2407717A1/en active Granted
- 1978-10-31 NL NL7810818A patent/NL7810818A/en not_active Application Discontinuation
- 1978-10-31 CH CH1119878A patent/CH642847A5/en not_active IP Right Cessation
- 1978-11-02 JP JP13564378A patent/JPS5476830A/en active Granted
- 1978-11-03 BE BE191526A patent/BE871753A/en not_active IP Right Cessation
- 1978-11-03 AU AU41316/78A patent/AU524988B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AU4131678A (en) | 1979-05-17 |
| DE2846335A1 (en) | 1979-05-10 |
| FR2407717B1 (en) | 1980-10-03 |
| AU524988B2 (en) | 1982-10-14 |
| BE871753A (en) | 1979-03-01 |
| CH642847A5 (en) | 1984-05-15 |
| ZA785998B (en) | 1980-06-25 |
| FR2407717A1 (en) | 1979-06-01 |
| IT1143611B (en) | 1986-10-22 |
| NL7810818A (en) | 1979-05-07 |
| JPS5476830A (en) | 1979-06-19 |
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